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The abilities of monoclonal antibodies (MAbs) that bind to defined sequential

The abilities of monoclonal antibodies (MAbs) that bind to defined sequential epitopes within the dengue virus (DENV) nonstructural-1 (NS1) glycoproteins to cross-react with epitopes within the DENV envelope (E) glycoproteins were investigated. and highly virulent (M2) DENV-2 strains. These cross-reactions using the E glycoprotein accord using the observation that MAb 1G5.3 caused dramatic and lethal antibody-enhanced replication (AER) of the DENV-2 stress in vivo. As well as in AER research of the DENV strains using MAb 1G5 vivo.4-A1-C3, these total outcomes may take into account the improved pathogenic capacities of such strains, which will probably have got important implications for vaccines and pathogenesis. The spread of dengue hemorrhagic fever/dengue surprise syndrome (DHF/DSS) across the world provides occurred through transport of the even more virulent viral strains from Southeast Asia, where DHF/DSS may be the main reason behind juvenile hospitalization (14). Strains of dengue trojan type 2 (DENV-2) and DENV-3 are connected with Bay 65-1942 most situations of DHF/DSS, but a couple of no dependable virulence marker sequences on pathogenic DENV strains. Almost all DHF/DSS situations derive from sequential an infection using a virulent DENV stress of another serotype following the preliminary an infection (14, 15). Individual antibodies bind to common epitopes over the heterologous trojan, and of cross-neutralization instead, they can Bay 65-1942 improve the replication of DENV strains in focus on Fc receptor-bearing monocytes/macrophages, which includes been hypothesized to take into account DHF/DSS (15). Nearly all proof for antibody-enhanced replication (AER) from the DENVs originates Fzd10 from in vitro research, but dramatic AER of the DENV-2 stress in addition has been showed in vivo (10; find below). Individual immunoglobulin G (IgG) polyclonal antibodies (PAbs) produced against the DENV non-structural-1 (NS1) glycoprotein could possibly be detected only through the convalescent stage of principal DENV attacks but had been strongly identified through the severe stage of supplementary DENV attacks (37), recommending that they could are likely involved in the pathogenesis of DHF/DSS. During DENV infections, human PAb reactions were generated to multiple acidic (E or D)-aliphatic/aromatic (G, A, I, L or V/F, W, or Y)-fundamental (K or R) (ELK-type tri-amino acid) motifs present in either orientation (ELK/KLE-type motifs) within the DENV NS1 glycoproteins, and these reactions Bay 65-1942 were higher in DSS individuals than in individuals with slight disease (dengue fever [DF]) (7). Monoclonal antibody (MAb) 1G5.4-A1-C3 displayed the same reaction pattern as that for human being DSS patient PAbs against multiple ELK/KLE-type epitopes within the DENV-2 NS1 glycoprotein, and therefore the cross-reaction of this MAb with additional DENV proteins and human proteins is likely to be highly relevant in studies of DHF/DSS pathogenesis (7, 9). Three additional MAbs generated to the DENV-2 NS1 protein also identified short sequential amino acid sequences. MAb 1C6.3 reacted more specifically with multiple KELK-type motifs present in either orientation (KELK/KLEK-type motifs), MAb 3D1.4 recognized the LX1 (113-YSWKTWG-119) epitope, and MAb 1G5.3 recognized the 24C (301-TTASGKLIT-309) epitope (7, 9, 12). Mouse PAbs and MAbs generated to the DENV-2 NS1 glycoprotein precipitated the DENV-2 NS1 glycoprotein, together with lower concentrations of the DENV-2 envelope (E) and premembrane (prM) glycoproteins (35), suggesting that common epitopes happen on these viral glycoproteins. This was further supported from the finding that PAbs, and some MAbs, raised to the DENV-2 NS1 glycoprotein could generate dramatic (>100,000-collapse) and lethal AER of a DENV-2 strain in vivo (10). Many epitope-reactive MAbs, defined by neutralizing DENV type or complex as well as by flavivirus subgroup and group, have been located within the E glycoprotein. These epitopes were recognized by either the generation of escape mutations (13, 24, 25, 36), binding studies using recombinant protein fragments (26), reactions with recombinant constructs comprising specific amino acid substitutions (4, 6, 17, 38, 39), or reactions with synthetic peptide sequences (1, 8, 18). From these studies, epitopes identified by neutralizing.